Nirmatrelvir Plus Ritonavir for Ambulatory COVID-19: Expanding Evidence, Expanding Role
Authors: George L. Anesi, Christina Maguire
Journal: Annals of Internal Medicine (2022)

EditorialsJanuary 2023Nirmatrelvir Plus Ritonavir for Ambulatory COVID-19: Expanding Evidence, Expanding RoleFREEGeorge L. Anesi, MD, MSCE, MBE, Christina Maguire, PharmD, BCIDPGeorge L. Anesi, MD, MSCE, MBEDivision of Pulmonary, Allergy, and Critical Care, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, Christina Maguire, PharmD, BCIDPDepartment of Pharmacy, Penn Presbyterian Medical Center, Philadelphia, PennsylvaniaAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/M22-3427 SectionsAboutVisual AbstractPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail The prevention and treatment algorithm for COVID-19 begins with vaccination. Although vaccines have proved exceptional, the need for effective therapeutics for SARS-CoV-2 infection remains: Vaccine and booster uptake is heterogeneous, infection can occur in vaccinated persons, protection can wane with time, additional immune-evasive subvariants continue to emerge, some people are at higher risk for severe disease, and immunocompromised persons may mount a suboptimal protective response even if they are vaccinated or have previously been infected. Based on evidence and regulatory approval, the ambulatory COVID-19 treatment algorithm has included the antivirals nirmatrelvir plus ritonavir (a boosted SARS-CoV-2 protease inhibitor), molnupiravir, and remdesivir and an ever-evolving (and shrinking) list of monoclonal antibodies.In their article, Dryden-Peterson and colleagues report the results of a retrospective cohort study to assess the real-world efficacy of nirmatrelvir plus ritonavir for early outpatient COVID-19 in an era of prevalent SARS-CoV-2 immunity and immune-evasive Omicron subvariants (1). This study included more than 44 000 nonhospitalized adults aged 50 years or older with COVID-19. The primary exposure was a prescription for nirmatrelvir plus ritonavir within 2 days of diagnosis, mimicking an intention-to-treat analysis, and the primary outcome was hospitalization for any cause within 14 days of diagnosis or death from any cause within 28 days. The study was designed to emulate a clinical trial and used inverse probability weighting, a propensity score–matching approach, to account for potential bias in real-world prescribing decisions. The primary finding was an adjusted risk ratio for hospitalization or death of 0.56 (a 44% reduction and a number needed to treat of 239) favoring nirmatrelvir plus ritonavir.This study has several strengths. It seeks to answer an ever-evolving question: What is the real-world efficacy of nirmatrelvir plus ritonavir, the leading component of our outpatient COVID-19 armamentarium, in the setting of a changing population immunity and viral lineage landscape? The study was large, rigorously analyzed, and well presented.The retrospective approach is both an asset—in measuring real-world efficacy, which is perhaps what matters most from a population health standpoint—and a drawback, with the normal limitations of residual bias. There are 2 important retorts. First, the authors used a thoughtful, though not infallible, approach to risk adjustment, thus reducing confounding by indication. Second, immortal time bias was mitigated by the exclusion of patients from both groups who were hospitalized within 2 days of diagnosis. Additional limitations are a lack of safety outcomes and the exclusion of patients with relative contraindications to nirmatrelvir plus ritonavir, which excluded many immunosuppressed patients. As in all COVID-19 literature, the viral subvariants under study are, to some extent, out of date by the time the article goes to press. This study covered the Omicron subvariants BA.1, BA.2, and BA.2.12.1 as well as the start of the BA.5 era, but it did not include the rapidly emerging next era of increasingly immune-evasive subvariants, such as BA.4.6, BQ.1, BQ.1.1, and BA.2.75.2.The only published randomized controlled trial to evaluate nirmatrelvir plus ritonavir was the manufacturer-sponsored EPIC-HR (Evaluation of Protease Inhibition for COVID-19 in High-Risk Patients) study (2). This trial enrolled high-risk persons in the Delta era without previous self-reported COVID-19 or, importantly, vaccination. The group receiving nirmatrelvir plus ritonavir had a lower rate of all-cause 28-day hospitalization or mortality than the placebo group (0.72% vs. 6.45%; P < 0.001). As the pandemic continued to evolve, data reflecting broader comorbidities, vaccination status, and the Omicron era were needed. To expand the eligibility pool, a second manufacturer-sponsored trial, EPIC-SR (Evaluation of Protease Inhibition for COVID-19 in Standard-Risk Patients), was initiated that included unvaccinated persons without risk factors for severe disease and high-risk vaccinated persons. The results, available only via a manufacturer press release and not yet published or peer-reviewed, show that the trial was halted early for low rates of hospitalization and death, with no difference in the primary outcome of sustained alleviation of symptoms (3). Secondary analyses showed a nonsignificant reduction in hospitalizations and death compared with placebo for high-risk vaccinated patients.In one Omicron-era retrospective study of adults aged 18 years or older, nirmatrelvir plus ritonavir was associated with a 45% relative risk reduction in all-cause 30-day emergency department visits, hospitalization, and death (4). In a subsequent analysis among adults aged 40 years or older, the benefit of nirmatrelvir plus ritonavir in preventing hospitalization and death was confirmed primarily in those aged 65 years or older and not in those aged 40 to 64 years. Furthermore, the protective effect was amplified among persons aged 65 years or older who did not have prior immunity (5).The real-world event rates and relative risk reductions reported by Dryden-Peterson and colleagues were similar to other previously reported retrospective results in vaccinated persons (6). A smaller subgroup of unvaccinated persons in the present study had an 81% relative risk reduction in all-cause hospitalization and death, which correlates with EPIC-HR results from the Delta era but is a larger point estimate than those in subsequent studies in the Omicron era, all of which have low event rates and high numbers needed to treat.New results in the present study include a greater benefit in partially vaccinated persons, those who were vaccinated more than 20 weeks prior, and those with higher comorbidity scores and a trend toward benefit down to age 50 years. Immunocompromised persons were better represented in the overall sample than in prior studies, but subgroup analyses are not available. Although there are no head-to-head prospective comparisons, outcomes with nirmatrelvir plus ritonavir seem to be superior to those with molnupiravir (6), and administration is logistically easier than for outpatient intravenous remdesivir (7). Remaining questions include how nirmatrelvir plus ritonavir performs among immunocompromised persons and against immune-evasive and more virulent variants that have yet to emerge.Dryden-Peterson and colleagues' real-world efficacy data on nirmatrelvir plus ritonavir are timely. As this editorial was being written, the Omicron subvariants BQ.1 and BQ.1.1 were crowding out BA.5 as the dominant variants in the United States. Preliminary data, which have not yet been published or peer-reviewed, suggest that new convergent mutations in these next subvariants will cause significant immune evasion to bebtelovimab, motivating the recent regulatory removal of this last remaining monoclonal antibody in use for treatment in the United States (8), and to tixagevimab–cilgavimab, which is used for prophylaxis in immunocompromised persons (9). These findings further elevate the stature of nirmatrelvir plus ritonavir in the ambulatory COVID-19 treatment algorithm, particularly for persons older than 65 years (possibly 50 years) with multiple risk factors for severe disease and those with suboptimal preexisting immunity, but less so for immunocompetent young persons given the extremely low event rates in the Omicron era. These developments are particularly concerning for immunocompromised persons who rely most on antibody-based prevention and treatment due to poor immunogenicity from vaccines and prior infection and high risk for severe disease. Clinicians now face the dilemma of providing therapy to prevent progression while accounting for severe and sometimes insurmountable drug–drug interactions. Multidisciplinary collaboration, including input from transplant specialists and pharmacists, is needed to navigate these scenarios. Uptake of prescription of nirmatrelvir plus ritonavir is suboptimal, sometimes in ways that exacerbate pandemic disparities (10). The present study and the state of the evolving pandemic offer further motivation to rectify that.References1. Dryden-Peterson S, Kim A, Kim AY, et al. Nirmatrelvir plus ritonavir for early COVID-19 in a large U.S. health system. A population-based cohort study. Ann Intern Med. 2023;176:77-84. doi:10.7326/M22-2141 LinkGoogle Scholar2. Hammond J, Leister-Tebbe H, Gardner A, et al; EPIC-HR Investigators. Oral nirmatrelvir for high-risk, nonhospitalized adults with Covid-19. N Engl J Med. 2022;386:1397-1408. [PMID: 35172054] doi:10.1056/NEJMoa2118542 CrossrefMedlineGoogle Scholar3. Pfizer. Pfizer Reports Additional Data on PAXLOVID™ Supporting Upcoming New Drug Application Submission to U.S. FDA [press release]. 14 June 2022. Accessed at www.pfizer.com/news/press-release/press-release-detail/pfizer-reports-additional-data-paxlovidtm-supporting on 13 November 2022. Google Scholar4. Ganatra S, Dani SS, Ahmad J, et al. Oral nirmatrelvir and ritonavir in non-hospitalized vaccinated patients with Covid-19. Clin Infect Dis. 2022. [PMID: 35986628] doi:10.1093/cid/ciac673 CrossrefMedlineGoogle Scholar5. Arbel R, Wolff Sagy Y, Hoshen M, et al. Nirmatrelvir use and severe Covid-19 outcomes during the Omicron surge. N Engl J Med. 2022;387:790-8. [PMID: 36001529] doi:10.1056/NEJMoa2204919 CrossrefMedlineGoogle Scholar6. Wong CKH, Au ICH, Lau KTK, et al. Real-world effectiveness of molnupiravir and nirmatrelvir plus ritonavir against mortality, hospitalisation, and in-hospital outcomes among community-dwelling, ambulatory patients with confirmed SARS-CoV-2 infection during the Omicron wave in Hong Kong: an observational study. Lancet. 2022;400:1213-22. [PMID: 36216007] doi:10.1016/S0140-6736(22)01586-0 CrossrefMedlineGoogle Scholar7. Gottlieb RL, Vaca CE, Paredes R, et al; GS-US-540-9012 (PINETREE) Investigators. Early remdesivir to prevent progression to severe Covid-19 in outpatients. N Engl J Med. 2022;386:305-15. [PMID: 34937145] doi:10.1056/NEJMoa2116846 CrossrefMedlineGoogle Scholar8. U.S. Food and Drug Administration. FDA announces bebtelovimab is not currently authorized in any US region. 30 November 2022. Accessed at www.fda.gov/drugs/drug-safety-and-availability/fda-announces-bebtelovimab-not-currently-authorized-any-us-region on 30 November 2022. Google Scholar9. Cao Y, Jian F, Wang J, et al. Imprinted SARS-CoV-2 humoral immunity induces convergent Omicron RBD evolution. bioRxiv. Preprint posted online 4 October 2022. doi:10.1101/2022.09.15.507787 CrossrefGoogle Scholar10. Gold JAW, Kelleher J, Magid J, et al. Dispensing of oral antiviral drugs for treatment of COVID-19 by zip code-level social vulnerability - United States, December 23, 2021-May 21, 2022. MMWR Morb Mortal Wkly Rep. 2022;71:825-9. [PMID: 35737571] doi:10.15585/mmwr.mm7125e1 CrossrefMedlineGoogle Scholar Comments0 CommentsSign In to Submit A Comment Binh T. Ngo, Marc S. RendellKeck USC School of Medicine and the Rose Salter Medical Research Foundation12 December 2022 Comparability of Cohorts is Essential Given the highly variable outcomes of the phases of Covid-19 ranging from asymptomatic infection to death, it has proven challenging to create randomized placebo controlled studies with sufficient statistical power to prove benefit of treatments. Furthermore, the severity of Omicron illness is significantly reduced compared to prior SARS-Cov-2 variants from the original Wuhan strain (1). Consequently, from a clinical trials standpoint, a very large number of subjects is required to assess a meaningful change in Covid hospitalizations and mortality due to an intervention. Nirmatrelvir-ritonavir was endorsed by the NIH and CDC on the basis of a single randomized placebo controlled study in 2246 high risk non-hospitalized Covid-19 patients (2). Yet Pfizer subsequently shut down a study of standard risk Covid-19 patients as well as a prevention study for contacts of Covid-19 patients claiming that benefit did not reach statistical significance in either study(3,4). Therefore, the current standard of evidence for benefit of preventive measures or treatment of Covid-19 has shifted away from randomized control studies with insufficient subject numbers toward large scale population studies based on mining of massive clinical databases. So, for example, the current recommendations for mRNA SARS-Cov-2 vaccination are based on observation of results primarily in the Israeli and British populations where their National Health systems affords comprehensive homogeneous data. The present study in 117,385 Mass General-Brigham patients is of sufficient magnitude to evaluate the real world effect of nirmatrelvir-ritonavir and is unquestionably positive. However, in assessing the results, it is also essential to recognize the advantage of randomized trials in providing relatively comparable study cohorts and in collecting sufficient information to validate comparability. Dryden-Petersen et al do not fully describe what alternative treatments were offered to those patients who did not receive nirmatrelvir-ritonavir; furthermore they leave out the very critical patient demographic of duration of symptoms prior to administration of nirmatrelvir-ritonavir. COVID-19 is a multiphasic disease, with the phase of viral replication ending typically in 5-7 days (5). The antiviral treatments which have been successful have typically been administered no later than 5 days from initial symptoms. In the case of nirmatrelvir-ritonavir the initial successful randomized control study included patients with only 3-day duration of symptoms (2). Certainly, Dryden-Petersen et al should provide complete data comparing duration of symptoms in the nirmatrelvir-ritonavir cohort compared to those patients who did not receive that treatment. REFERENCES 1) Iuliano AD, Brunkard JM, Boehmer TK, Peterson E, Adjei S, et al. Trends in disease severity and health care utilization during the early omicron variant period compared with previous sars-cov-2 high transmission periods — United States, December 2020–January 2022. MMWR Morb Mortal Wkly Rep 2022;71:146–152 2) Hammond J, Leister-Tebbe H, Gardner A, Abreu P, Bao W, et al. Oral nirmatrelvir for high-risk, nonhospitalized adults with Covid-19. N Engl J Med 2022;386:1397-1408 3) https://www.cnbc.com/2022/06/14/pfizer-stops-enrollment-in-covid-antiviral-trial-in-standard-risk-population-.html 4) https://www.reuters.com/business/healthcare-pharmaceuticals/pfizer-says-covid-treatment-paxlovid-fails-prevent-infection-household-members-2022-04-29/ 5) Griffin DO, Brennan-Rieder D, Ngo B, et al. The Importance of Understanding the Stages of COVID-19 in Treatment and Trials. AIDS Rev. 2021 ;23(1):40-47 Author, Article, and Disclosure InformationAuthors: George L. Anesi, MD, MSCE, MBE; Christina Maguire, PharmD, BCIDPAffiliations: Division of Pulmonary, Allergy, and Critical Care, University of Pennsylvania Perelman School of Medicine, Philadelphia, PennsylvaniaDepartment of Pharmacy, Penn Presbyterian Medical Center, Philadelphia, PennsylvaniaAcknowledgment: The authors thank the Penn Medicine COVID-19 Therapeutics Committee, membership in which has afforded them the ability and privilege to rigorously evaluate rapidly emerging evidence to guide the care of their patients since the start of the pandemic.Grant Support: Dr. Anesi is supported by the National Institutes of Health (K23HL161353).Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M22-3427.Corresponding Author: George L. Anesi, MD, MSCE, MBE, Division of Pulmonary, Allergy, and Critical Care, University of Pennsylvania Perelman School of Medicine, 3400 Spruce Street, 5037 Gates Building, Philadelphia, PA 19104; e-mail, george.anesi@pennmedicine.upenn.edu.This article was published at Annals.org on 13 December 2022. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetailsSee AlsoNirmatrelvir Plus Ritonavir for Early COVID-19 in a Large U.S. Health System Scott Dryden-Peterson , Andy Kim , Arthur Y. Kim , Ellen C. Caniglia , Inga T. Lennes , Rajesh Patel , Lindsay Gainer , Lisa Dutton , Elizabeth Donahue , Rajesh T. Gandhi , Lindsey R. Baden , and Ann E. Woolley Metrics January 2023Volume 176, Issue 1Page: 133-134KeywordsCOVID-19Infectious diseases ePublished: 13 December 2022 Issue Published: January 2023 Copyright & PermissionsCopyright © 2022 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...